Pharmacological stimulation of group I metabotropic glutamate receptors (group I mGluRs) elicits irreversible epileptiform activity in the hippocampal slices; this enduring effect of group I mGluR constitutes a novel model of epileptogenesis. Our studies show that the induction of group I mGluR-mediated epileptiform events is dependent on mRNA translation protein synthesis. Furthermore, our recent data suggest that the group I mGluR-induced mRNA translation that underlies epileptogenesis is normally repressed by the Fragile X mental retardation protein (FMRP). By restricting the translation process, FMRP serves as a safe-guard against the induction of group I mGluR-mediated epileptiform discharges in normal subjects. Fragile X syndrome (FXS), the most common hereditary form of mental retardation, is caused by a loss of FMRP function. In vivo and in vitro experiments using the Fragile X model mouse suggest that the propensity for epileptogenesis, presumably mediated by group I mGluRs, is significantly enhanced. This finding mirrors the clinical condition, where FXS patients have increased likelihood of epilepsy compared to the general population. The overall goals of the proposed research are to (I) elucidate the molecular and cellular signaling mechanisms underlying epileptogenesis in the Fragile X model preparation and (II) to identify conditions under which group I mGluR activation can cause epileptogenesis in normal, wild type preparations. Electrophysiological, pharmacological and biochemical techniques will be used to address three specific aims: (1) To assess the role of group I mGluRs in the synaptic induction of epileptiform discharges in the Fragile X model preparation (2) To characterize the synaptic and cellular plasticity, elicited by the inducing synaptic stimulation, that is necessary for the maintenance of epileptiform discharges in the Fragile X model preparation, and (3) To define the signaling mechanisms through which epileptiform discharges are elicited in the wild type preparation by group I mGluR stimulation. The relevance of the group I model of epileptogenesis to epilepsy in Fragile X syndrome will be further assessed. Results from the proposed study will provide fundamental information on the role of group I mGluR in the development of epileptogenesis. Such information will be useful in the design of rational therapeutic approaches to combat epilepsy, particularly in patients with Fragile X syndrome.